Although the role of certain types of human papillomavirus (HPV) in the etiology of cervical cancer is well-established, the involvement of HPV infection in squamous cell carcinoma of extragenital sites, such as the head and neck, is presently under extensive investigation. Prior research indicates that immunosuppression may contribute to the severity and progression of HPV-related lesions. Accumulating data also indicate that psychosocial (e.g., stress) and behavioral (e.g., smoking, alcohol use) factors are associated with immunosuppression and may adversely affect the immune system's ability to control and resolve HPV infection. Thus, the objective of the proposed project is to evaluate cellular immune response and potential moderators of host immunity among two groups: 1) 50 patients with premalignant lesions of the head and neck; and 2) 50 patients referred for definitive management of head and neck squamous cell carcinoma (HNSCC) who have not yet started treatment. Specific aims of the proposed project are: 1) to assess the prevalence of HPV in premalignant lesions of the head and neck in comparsion to the prevalence of HPV in head and neck tumors; 2) to evaluate specific cellular immunity to HPV in this population using an innovative assay that has demonstrated clinical relevance to disease progression in other cancer contexts (e.g., cervical); and, 3) to examine potential moderators of cellular immune response, such as behavioral (e.g., tobacco and alcohol use) and psychological (e.g., stress) risk factors. The proposed project will utilize a longitudinal, prospective design. Participants will complete a brief psychosocial and behavioral assessment and provide a blood sample for immunologic assays. A sample of cells will be obtained from the lesion or tumor site using a small cytobrush for HPV typing. Self-reported data to be collected include demographic variables, behavioral risk factors (e.g., tobacco and alcohol use), and psychosocial measures (e.g., distress, depression). Immune status will be assessed using functional (e.g.,T-cell proliferative response to HPV16, a specific marker of immunocompetence shown to be associated with viral clearance and disease regression) and quantitative (e.g., enumeration of lymphocyte subsets) assays. Follow-up assessments of HPV status, immunologic measures, and psychosocial and behavioral risk factors will be obtained 1-year post-baseline in order to examine potential associations with clinical outcomes.